The present invention concerns new biomaterials essentially constituted by esterified derivatives of hyaluronic acid or by cross-linked derivatives of hyaluronic acid for use in the surgical sector, particularly for use in the prevention of post-surgical adhesions.
Postoperative adhesion formation is a common complication in abdominal or pelvic surgery which may lead to a substantial morbidity. Many factors may influence the development of adhesions: mechanical trauma, chemical agents, drying of serosa in combination with blood, ischemia, infection and foreign material are all known to increase adhesion formation. Other causes are intraabdominal inflammatory diseases and congenital abnormalities. The pathophysiological mechanism still remain unclear, but a central common pathway in which peritoneal fibrinolysis plays an important role has been suggested.
The surgical trauma of the tissue causes the release of a serosanguinous exudate which forms a fibrinous bridge that persists several days during which cell growth occurs. If the exudate is not absorbed or lysed within this period, it becomes ingrown with fibroblasts and subsequent collagen deposition leads to the formation of a permanent scar connecting the two adjacent surfaces, called an adhesion. Thus, adhesion formation seems to be a result of an inflammatory response.
In this latter case, the research has mainly focused on the search for bioabsorbable materials with a short time of in vivo persistence, to act as barriers to adhesion formation until healing has occurred; in order to obviate the problems caused by non-absorbable materials (infection, calcification of the implants, scar formation, etc.).
One particularly promising polymer is Hyaluronic Acid (HA), a component of extracellular matrix ubiquitously found within the human body. Hyaluronic Acid solutions have been shown to reduce postoperative adhesion formation after abdominal surgery (Urman, B. et al., Effect of Hyaluronic Acid on Postoperative Intraperitoneal Adhesions Formation in the Rat Model, Fertil. Steril. 1991; 56:563; Shushan A. et al., Hyaluronic Acid for Preventing Experimental Postoperative-intraperitoneal Adhesions, J. Reprod. Med. 1994; 39:398) and orthopaedic operation (Hagberg, L, Gerdin, B., Sodium Hyaluronate as an adjunctive in adhesion prevention after flexor tendon surgery in rabbits, J. Hand. Surg. 1992; 17A:935).
Fidia Advanced Biopolymers has developed chemical derivatives of hyaluronic acid, i.e. internal esters (ACP series) and esters with non-active alcohols (HYAFF series) Rastrelli, A. et al., Hyaluronic Acid Esters, A New Class of Semisynthetic Biopolymers: Chemical and Physico-chemical Properties, Clinical Implant Materials, Advanced in Biomaterials, G. Heinrike, V. Sollz and AJC Lee (Eds), Elsevier, Amsterdam 1990; 9:199-205, which display physico-chemical properties different from that of HA (i.e. higher residence time and ability to be manufactured to produce devices, but possessing tolerability and biocompatibility properties typical of the original biological polymer). Moreover, these derivatives are characterized from a chemical and toxicological point of view.
The aim of the present invention has been to develop batches of derivatives of hyaluronic acid such as ACP gel and HYAFF in an attempt to evaluate the effect in adhesion prevention.
The onset of adherences, or fibrous masses which form between adjacent tissues affected by trauma or ischemia following surgery, is still one of the most serious complications in numerous surgical procedures. A large number of methods have been proposed to avoid this complication, but the problem has remained mainly unsolved.
One proposed method has been the use of suspensions of dextran (dizerega G. S., xe2x80x9cContemporary adhesion preventionxe2x80x9d Fertility and Sterility, Vol. 61, No. 2, February ""94) injected into the peritoneal cavity after surgery. The clinical results of the use of such dextran solutions have been largely discordant. Moreover, the use of solutions of dextran has been accompanied by frequent complications, including edema, abdominal pain and dyspnea.
The use of barriers in the form of defined structures (e.g. meshes, membranes) (dizerega G. S., xe2x80x9cContemporary adhesion preventionxe2x80x9d Fertility and Sterility, Vol. 61, No. 2, February ""94) or viscous gels (Genzyme U.S. Pat. No. 4,937,270xe2x80x94U.S. Pat. No. 5,017,229) placed between the injured organs has also been proposed. However, these barriers have generally proved ineffective because they provoke ischemic or inflammatory reactions due to the presence of foreign bodies. The only materials currently approved for clinical use are barriers based on oxidized regenerated cellulose (INTERCEED(copyright)) and barriers based on expanded polytetrafluorine ethylene (e-PTFE) (U.S. Pat. Nos. 4,478,665 and 4,482,516) or polyethylene or polypropylene.
In addition to the fact that clinical investigations into the efficacy of such barriers have produced highly discordant results, it must also be noted that both of the aforesaid materials are associated with major contraindications. The use of barrier membranes of e-PTFE or polyethylene or polypropylene involves the implantation of a synthetic material which is foreign to the human body and not biodegradable, and which may require a second surgical operation to remove or reposition the barrier membrane because of undesirable inflammatory-type reactions.
In preclinical and clinical models, meshes based on oxidized regenerated cellulose have proved to be efficacious in preventing the formation of adherences, but only if their application is preceded by thorough hemostasis.
The use of viscous solutions of high-molecular-weight hyaluronic acid (HA) has, therefore, been proposed as an aid in the prevention of adherence (Grainger D. A. et al., xe2x80x9cThe use of hyaluronic acid polymers to reduce postoperative adhesionsxe2x80x9d, J. of Gynecol. Surg., Vol. 7, No. 2, 1991; Hurman B. et al., xe2x80x9cEffect of hyaluronic acid on postoperative intraperitoneal adhesion formation in the rat modelxe2x80x9d, Fertility and Sterility, Vol. 56, No. 3, September 1991; Shushan A. et al., xe2x80x9cHyaluronic acid for preventing experimental postoperative intraperitoneal adhesions:, J. of Reproductive Med., Vol. 39, No. 5, May 1994; Mitchell J. D. et al., xe2x80x9cReduction in experimental pericardial adhesions using a hyaluronic acid bioabsorbable membranexe2x80x9d, Eur. J. Cardio-thorac. Surg., 8, 149-152, 1994). Hyaluronic acid as such, however, is characterized by very rapid absorption times which are incompatible with the residence time necessary to prevent adhesion. Moreover, natural hyaluronic acid cannot be processed and as such cannot be transformed into biomaterial form. In order to prolong its degradation times and enable it to be processed into various physical forms for use in different surgical sectors, esters of hyaluronic acid and cross-linked derivatives of hyaluronic acid have been developed. The preparation of esters of hyaluronic acid, wherein all or part of the carboxy groups are esterified, the preparation of cross-linked derivatives of hyaluronic acid, wherein part of the carboxy groups undergo cross-linking and their uses in the pharmaceutical, cosmetic and surgical sectors and in that of biodegradable plastic materials are described in U.S. Pat. Nos. 4,851,521 and 4,965,353, EP 0 216 453 and EP 0 341 745.
The present invention provides biomaterials for use in the prevention of post-surgical adhesions. The biomaterials are comprised of benzyl esters of hyaluronic acid and/or internally cross-linked derivatives of hyaluronic acid and may be in the form of gels, membranes, woven tissues or meshes and nonwoven tissues.